Pharmaceutical for prophylaxis or treatment of hypertension

ABSTRACT

A pharmaceutical for the prophylaxis or treatment of hypertension or a disease derived from hypertension. The pharmaceutical is characterized by comprising (i) a specific mineralocorticoid receptor antagonist and (ii) one or more components selected from the following components (A) to (C), for administration simultaneously or separately at a time interval: (A) an angiotensin II receptor antagonist, (B) a calcium antagonist, and (C) a diuretic.

TECHNICAL FIELD

The present invention relates to a pharmaceutical for the prophylaxis ortreatment of hypertension, a heart disease [angina pectoris, myocardialinfarction, arrhythmia (including sudden death), heart failure, orcardiac hypertrophy], a kidney disease (diabetic nephropathy,glomerulonephritis, or nephrosclerosis), a cerebrovascular disease(cerebral infarction or intracerebral hemorrhage), or a vasculardisorder (arteriosclerosis, restenosis after PTCA, or peripheralcirculatory disturbance).

BACKGROUND ART

At present, angiotensin II receptor antagonists and calcium antagonistsare widely used as pharmaceuticals for the treatment or prophylaxis ofhypertension, a heart disease, or the like.

Mineralocorticoid receptors (MR) (aldosterone receptors) are known toplay an important role in regulating electrolyte balance and bloodpressure in the body, and MR antagonists having a steroidal structuresuch as spironolactone and eplerenone are known to be useful for thetreatment of hypertension and heart failure.

Angiotensin II receptor antagonists which are renin-angiotensin systeminhibitors are particularly effective in renin-dependent hypertensionand exhibit a protective activity against cardiovascular disorders andkidney disorders. Further, calcium antagonists antagonize (inhibit) thefunction of calcium channels so as to have a natriuretic activity inaddition to a vasodilatory activity, and are therefore effective also influid retention (renin-independent) hypertension.

Accordingly, it is expected that by using an MR antagonist and anangiotensin II receptor antagonist or a calcium antagonist incombination, multiple causes of high blood pressure can be suppressedsimultaneously, and a stable and sufficient therapeutic or prophylacticeffect on hypertension is exhibited regardless of the causes of thedisease.

Further, also diuretics are widely used as pharmaceuticals for thetreatment or prophylaxis of hypertension, a heart disease, or the like.Diuretics are effective in the treatment of hypertension because oftheir diuretic effect. Therefore, it is expected that by using an MRantagonist and a diuretic in combination, multiple causes of high bloodpressure can be suppressed simultaneously because of the diureticactivity of the diuretic, and a stable and sufficient therapeutic orprophylactic effect on hypertension is exhibited regardless of thecauses of the disease.

1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide(hereinafter referred to as “compound (I)”) is disclosed in PTL 1 andPTL 2, and is known to be useful for treating hypertension, diabeticnephropathy, and the like.

(5-Methyl-2-oxo-1,3-dioxolan-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate(hereinafter referred to as “olmesartan medoxomil”) is an angiotensin IIreceptor antagonist, and is known to be useful as a pharmaceutical fortreatment or the prophylaxis of hypertension, a heart disease, and thelike (PTL 3).

Olmesartan medoxomil is commercially available as Olmetec® tablet orBenicar®, each of which contains olmesartan medoxomil as an activeingredient in an amount of 5 mg, 10 mg, 20 mg, or 40 mg, and furthercontains low-substituted hydroxypropyl cellulose, hydroxypropylcellulose, crystalline cellulose, lactose, and magnesium stearate asadditives.

Further,3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (hereinafter referred to as “amlodipine”) is a knowncompound as an excellent calcium antagonist and is useful as apharmaceutical for the treatment or prophylaxis of hypertension, a heartdisease, and the like (PTL 4)

Amlodipine is commercially available as Norvasc® tablets, which containamlodipine besylate as an active ingredient in an amount of 3.47 mg or6.93 mg (2.5 mg or 5 mg in terms of amlodipine) and further containscrystalline cellulose, anhydrous calcium hydrogen phosphate,carboxymethyl starch sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium oxide, talc, and carnauba wax as additives. Further,6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonami de1,1-dioxide (hereinafter referred to as “hydrochlorothiazide”) is aknown compound as an excellent thiazide-based diuretic and is describedin, for example, PTL 5, and the like.

CITATION LIST Patent Literature

PTL 1: WO 2006/012642 (US Patent Publication No. US2008-0234270)

PTL 2: WO 2008/056907 (US Patent Publication No. US2010-0093826)

PTL 3: Japanese Patent No. 2082519 (U.S. Pat. No. 5,616,599)

PTL 4: Japanese Patent No. 1401088 (U.S. Pat. No. 4,572,909)

PTL 5: U.S. Pat. No. 3,025,292

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a pharmaceutical forthe prophylaxis or treatment of hypertension or a disease derived fromhypertension, more specifically, to provide a pharmaceutical for theprophylaxis and/or treatment of hypertension, a heart disease [anginapectoris, myocardial infarction, arrhythmia (including sudden death),heart failure, or cardiac hypertrophy], a kidney disease (diabeticnephropathy, glomerulonephritis, or nephrosclerosis), a cerebrovasculardisease (cerebral infarction or intracerebral hemorrhage), or a vasculardisorder (arteriosclerosis, restenosis after PTCA, or peripheralcirculatory disturbance) (particularly a pharmaceutical for theprophylaxis or treatment of hypertension).

Solution to Problem

As a result of intensive studies to achieve the above object, thepresent inventors found that by combining a specific MR antagonist withan angiotensin II receptor antagonist, a calcium antagonist, or adiuretic, an excellent blood pressure lowering activity is exhibited.Further, the present inventors found that such a pharmaceutical isextremely effective in the prophylaxis and/or treatment of hypertension,a heart disease [angina pectoris, myocardial infarction, arrhythmia(including sudden death), heart failure, or cardiac hypertrophy], akidney disease (diabetic nephropathy, glomerulonephritis, ornephrosclerosis), a cerebrovascular disease (cerebral infarction orintracerebral hemorrhage), or a vascular disorder (arteriosclerosis,restenosis after PTCA, or peripheral circulatory disturbance). Thepresent invention has been completed based on the above findings.

That is, the present invention provides the following (1) to (13).

(1) A pharmaceutical for the prophylaxis or treatment of hypertension ora disease derived from hypertension, characterized by comprising

(i) a mineralocorticoid receptor antagonist which contains a substanceselected from the group consisting of a compound represented by thefollowing formula (I):

and an atropisomer thereof, and a pharmacologically acceptable saltthereof, and

(ii) one or more components selected from the following components (A)to (C), for administration simultaneously or separately at a timeinterval:

(A) one or more angiotensin II receptor antagonists;

(B) one or more calcium antagonists comprising a substance selected fromthe group consisting of a 1,4-dihydropyridine-based compound and apharmacologically acceptable salt thereof; and

(C) one or more diuretics.

(2) A pharmaceutical for the prophylaxis or treatment of a diseaseselected from the group consisting of hypertension, a heart disease,angina pectoris, myocardial infarction, arrhythmia, sudden death, heartfailure, cardiac hypertrophy, a kidney disease, diabetic nephropathy,glomerulonephritis, nephrosclerosis, a cerebrovascular disease, cerebralinfarction, intracerebral hemorrhage, and a vascular disorder(arteriosclerosis, restenosis after PTCA, or peripheral circulatorydisturbance), comprising one or more components selected from component(A), component (B), and component (C), and the mineralocorticoidreceptor antagonist according to the above (1) as active ingredients.

(2-1) A pharmaceutical for the prophylaxis or treatment of hypertensionand/or diabetic nephropathy, comprising one or more components selectedfrom component (A), component (B), and component (C), and themineralocorticoid receptor antagonist according to the above (1) asactive ingredients.

(2-2) A pharmaceutical for treating hypertension, comprising one or morecomponents selected from component (A), component (B), and component(C), and the mineralocorticoid receptor antagonist according to theabove (1) as active ingredients.

(2-3) A pharmaceutical for treating diabetic nephropathy, containing oneor more components selected from a component (A), a component (B), and acomponent (C), and the mineralocorticoid receptor antagonist accordingto the above (1) as active ingredients.

(3) The pharmaceutical according to the above (1) or (2), wherein thepharmaceutical is in the form of a pharmaceutical composition.

(4) The pharmaceutical according to any one of the above (1) to (3),wherein the angiotensin II receptor antagonist is(5-methyl-2-oxo-1,3-dioxolan-4-yl) methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate

(5) The pharmaceutical according to any one of the above (1) to (4),wherein the calcium antagonist is a calcium antagonist selected from thegroup consisting of azelnidipine, amlodipine, benidipine, nitrendipine,manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine,lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine,barnidipine, felodipine, clevidipine, lacidipine, and nilvadipine.

(6) The pharmaceutical according to any one of the above (1) to (4),wherein the calcium antagonist is amlodipine.

(7) The pharmaceutical according to any one of the above (1) to (6),wherein the diuretic is a diuretic selected from the group consisting ofhydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide,trichloromethiazide, cyclopenthiazide, polythiazide, ethiazide,cyclothiazide, bendroflumethiazide, and hydroflumethiazide.

(8) The pharmaceutical according to any one of the above (1) to (6),wherein the diuretic is hydrochlorothiazide.

(9) The pharmaceutical according to the above (1), wherein themineralocorticoid receptor antagonist is(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamiderepresented by the following formula (Ia):

and the calcium antagonist is amlodipine.

(10) The pharmaceutical according to any one of the above (1) to (9),wherein the pharmaceutical is formulated as a single preparation.

(11) A pharmaceutical comprising a substance selected from the groupconsisting of compound (I), an atropisomer thereof, and apharmacologically acceptable salt thereof for use in combination withone or more components selected from the following components (A) to(C):

(A) one or more angiotensin II receptor antagonists;

(B) one or more calcium antagonists comprising a substance selected fromthe group consisting of a 1,4-dihydropyridine-based compound and apharmacologically acceptable salt thereof; and

(C) one or more diuretics.

(12) A pharmaceutical which comprises a substance selected from thegroup consisting of a compound (I), an atropisomer thereof, and apharmacologically acceptable salt thereof, and enhances the activity ofcomponents (A) to (C) by comprising one or more components selected fromthe following components (A) to (C) in combination:

(A) one or more angiotensin II receptor antagonists;

(B) one or more calcium antagonists comprising a substance selected fromthe group consisting of a 1,4-dihydropyridine-based compound and apharmacologically acceptable salt thereof; and

(C) one or more diuretics.

(13) The pharmaceutical according to the above (11) or (12), wherein thecompound (I) is(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide.

Further, according to the present invention, use of a mineralocorticoidreceptor antagonist which comprises a substance selected from the groupconsisting of a compound represented by the above formula (I), anatropisomer thereof, and a pharmacologically acceptable salt thereof,and component (A), component (B), or component (C) for producing thepharmaceutical; and a prophylaxis or treatment method (particularly atreatment method) for a disease, including administering effectiveamounts of a mineralocorticoid receptor antagonist which comprises asubstance selected from the group consisting of a compound representedby the above formula (I), an atropisomer thereof, and apharmacologically acceptable salt thereof, and component (A), component(B) or component (C) to a warm-blooded animal (particularly a humanbeing) are provided.

According to preferred embodiments of the respective inventionsdescribed above, the pharmaceutical is provided as a pharmaceuticalcomposition comprising a mineralocorticoid receptor antagonist whichcomprises a substance selected from the group consisting of a compoundrepresented by the above formula (I), an atropisomer thereof, and apharmacologically acceptable salt thereof, and component (A), component(B) or component (C) as active ingredients, and this pharmaceuticalcomposition may comprise one or more pharmaceutical additives.

Advantageous Effects of Invention

A pharmaceutical comprising an angiotensin II receptor antagonist, acalcium antagonist, or a diuretic, and an MR antagonist as activeingredients of the present invention has an excellent blood pressurelowering activity and also has low toxicity, and therefore is useful asa pharmaceutical {preferably a prophylactic agent or a therapeutic agent(particularly a therapeutic agent) for hypertension, a heart disease[angina pectoris, myocardial infarction, arrhythmia (including suddendeath), heart failure, or cardiac hypertrophy], a kidney disease(diabetic nephropathy, glomerulonephritis, or nephrosclerosis), acerebrovascular disease (cerebral infarction or intracerebralhemorrhage), or a vascular disorder (arteriosclerosis, restenosis afterPTCA, or peripheral circulatory disturbance), more preferably aprophylactic agent or a therapeutic agent (particularly a therapeuticagent) for hypertension or a heart disease, and particularly preferablya prophylactic agent or a therapeutic agent (particularly a therapeuticagent) for hypertension}. Further, the pharmaceutical is preferably usedfor a warm-blooded animal, and more preferably used for a human being.

DESCRIPTION OF EMBODIMENTS

The pharmaceutical of the present invention is characterized bycomprising a mineralocorticoid receptor antagonist which comprises asubstance selected from the group consisting of a compound representedby the above formula (I), an atropisomer thereof, and apharmacologically acceptable salt thereof, and

(A) one or more angiotensin II receptor antagonists;

(B) one or more calcium antagonists comprising a substance selected fromthe group consisting of a 1,4-dihydropyridine-based compound and apharmacologically acceptable salt thereof; or

(C) one or more diuretics as active ingredients.

The compound represented by the above formula (I), an atropisomerthereof, or a pharmacologically acceptable salt thereof serving as anactive ingredient of the present invention is known, and can be producedby, for example, the method described in WO 2006/012642 (US PatentPublication No. US2008-0234270), WO 2008/056907 (US Patent PublicationNo. US2010-0093826), or the like. The compound (I) or an atropisomerthereof is preferably the following atropisomer compound (Ia).

As a substance selected from the compound represented by the aboveformula (I) or an atropisomer thereof, a hydrate or a solvate can alsobe used. As the compound represented by the above formula (I), anatropisomer in pure form or an arbitrary mixture of atropisomers canalso be used.

Examples of the angiotensin II receptor antagonist to be used as thecomponent (A) include biphenyl tetrazole compounds such as olmesartanmedoxomil, olmesartan cilexetil, losartan, candesartan cilexetil,valsartan, and irbesartan, biphenyl carboxylic acid compounds such astelmisartan, eprosartan, and azilsartan, and the angiotensin II receptorantagonist is preferably a biphenyl tetrazole compound, more preferablyolmesartan medoxomil, losartan, candesartan cilexetil, valsartan, orirbesartan, particularly preferably olmesartan medoxomil, losartan, orcandesartan cilexetil, and most preferably olmesartan medoxomil.

Olmesartan medoxomil is described in JP-A-5-78328, U.S. Pat. No.5,616,599, and the like, and its chemical name is(5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate,and olmesartan medoxomil as used herein encompasses a pharmacologicallyacceptable salt thereof.

Losartan (DUP-753) is described in JP-A-63-23868, U.S. Pat. No.5,138,069, and the like, and its chemical name is2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-methanol,and losartan as used herein encompasses a pharmacologically acceptablesalt thereof (losartan potassium salt or the like).

Candesartan cilexetil is described in JP-A-4-364171, EP-459136, U.S.Pat. No. 5,354,766, and the like, and its chemical name is1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzimidazole-7-carboxylate,and candesartan cilexetil as used herein encompasses a pharmacologicallyacceptable salt thereof.

Valsartan (CGP-48933) is described in JP-A-4-159718, EP-433983, and thelike, and its chemical name is(S)-N-valeryl-N-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl)valine, andvalsartan as used herein encompasses a pharmacologically acceptableester thereof or a pharmacologically acceptable salt thereof.

Irbesartan (SR-47436) is described in JP-T-4-506222, WO 91-14679, andthe like, and its chemical name is2-N-butyl-4-spirocyclopentane-1-[2′-(tetrazol-5-yl)bipheny1-4-ylmethyl]-2-imidazoline-5-one, and irbesartan as used hereinencompasses a pharmacologically acceptable salt thereof.

Eprosartan (SKB-108566) is described in U.S. Pat. No. 5,185,351 and thelike, and its chemical name is3-[1-(4-carboxyphenylmethyl)-2-n-butyl-imidazol-5-yl]-2-thienyl-methyl-2-propenoicacid, and eprosartan as used herein encompasses a carboxylic acidderivative thereof, a pharmacologically acceptable ester of a carboxylicacid derivative, or a pharmacologically acceptable salt thereof(eprosartan mesylate or the like).

Telmisartan (BIBR-277) is described in U.S. Pat. No. 5,591,762 and thelike, and its chemical name is4′-[[4-methyl-6-(1-methyl-2-benzimidazolyl)-2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylicacid, and telmisartan as used herein encompasses a carboxylic acidderivative thereof, a pharmacologically acceptable ester of a carboxylicacid derivative, or a pharmacologically acceptable salt thereof.

Azilsartan is described in JP-A-05-271228, U.S. Pat. No. 5,243,054, andthe like, and its chemical name is2-ethoxy-1{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-carboxylicacid.

Further, in the case where the above compounds have an asymmetriccarbon, the angiotensin II receptor antagonist of the present inventionalso encompasses optical isomers and mixtures of isomers thereof.Further, it also encompasses hydrates of the compounds.

The calcium antagonist containing a 1,4-dihydropyridine-based compoundto be used as the component (B) is a calcium antagonist characterized byhaving a 1,4-dihydropyridine partial structure or a partial structurechemically equivalent thereto in the molecule. As calcium antagonistscontaining a 1,4-dihydropyridine-based compound, various agents havebeen proposed and are actually used in clinical practice, and therefore,those skilled in the art can select a suitable agent exhibiting theeffect of the present invention. As a calcium antagonist containing a1,4-dihydropyridine-based compound, for example, azelnidipine,amlodipine, benidipine, nitrendipine, manidipine, nicardipine,nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine,nimodipine, aranidipine, efonidipine, barnidipine, felodipine,clevidipine, lacidipine, nilvadipine, or the like can be used, however,the calcium antagonist is not limited thereto.

The type of the pharmacologically acceptable salt of the1,4-dihydropyridine-based compound is not particularly limited and canbe suitably selected by those skilled in the art. The pharmacologicallyacceptable salt may be either an acid addition salt or a base additionsalt. Examples thereof include metal salts including alkali metal saltssuch as sodium salts, potassium salts, and lithium salts, alkaline earthmetal salts such as calcium salts and magnesium salts, aluminum salts,iron salts, zinc salts, copper salts, nickel salts, and cobalt salts;base addition salts such as amine salts including inorganic salts suchas ammonium salts and organic salts such as t-octyl amine salts,dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycinealkyl ester salts, ethylenediamine salts, N-methylglucamine salts,guanidine salts, diethylamine salts, triethylamine salts,dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts,chloroprocaine salts, procaine salts, diethanolamine salts,N-benzylphenethylamine salts, piperazine salts, tetramethyl ammoniumsalts, and tris(hydroxymethyl)aminomethane salts; mineral acid saltssuch as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides,nitrates, perchlorates, sulfates, and phosphates; sulfonates such asmethanesulfonates, trifluoromethanesulfonates, ethanesulfonates,benzenesulfonates, and p-toluenesulfonates; carboxylates such asbesylates, fumarates, succinates, citrates, tartrates, oxalates, andmaleates; and amino acid salts such as glutamates and aspartates,however, the salt is not limited thereto.

As the calcium antagonist containing a 1,4-dihydropyridine-basedcompound, a hydrate or a solvate of the above-mentioned compound or apharmacologically acceptable salt thereof may be used. Further, thecalcium antagonist containing a 1,4-dihydropyridine-based compoundsometimes has one or more asymmetric carbon atoms in the molecule,however, an optical isomer or a stereoisomer such as a diastereoisomerin pure form based on the asymmetric carbon, or an arbitrary mixture ofstereoisomers or a racemic mixture, or the like can also be used as thecomponent (B). As the component (B),(±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylicacid 3-(1-diphenylmethylazetidin-3-yl)ester 5-isopropyl ester ispreferred.

The calcium antagonist containing a 1,4-dihydropyridine-based compoundis more preferably amlodipine, and can be easily produced according tothe method described in Japanese Patent No. 1401088 (U.S. Pat. No.4,572,909) or the like. Amlodipine can form pharmacologically acceptablesalts, and the present invention also encompasses these salts. Thepharmacologically acceptable salt may be either an acid addition salt ora base addition salt. Examples thereof include besylates,hydrochlorides, hydrobromides, fumarates, citrates, tartrates, maleates,camsilates, lactates, mesylates, nicotinates, and gluconates. The saltis not limited thereto, but is preferably a besylate.

The diuretic to be used as the component (C) is a known compound, and isdescribed in, for example, U.S. Pat. No. 2,554,816, U.S. Pat. No.2,980,679, U.S. Pat. No. 2,783,241, UK Patent No. 795,174, U.S. Pat. No.2,835,702, UK Patent No. 851,287, U.S. Pat. No. 3,356,692, U.S. Pat. No.3,055,904, U.S. Pat. No. 2,976,289, U.S. Pat. No. 3,058,882,Pharmacometrics, vol. 21, 607 (1982), U.S. Pat. No. 3,183,243, U.S. Pat.No. 3,360,518, U.S. Pat. No. 3,567,777, U.S. Pat. No. 3,634,583, U.S.Pat. No. 3,025,292, U.S. Pat. No. 3,108,097, U.S. Pat. No. 3,009,911,U.S. Pat. No. 3,265,573, U.S. Pat. No. 3,254,076, U.S. Pat. No.3,255,241, U.S. Pat. No. 3,758,506, U.S. Pat. No. 3,163,645, and thelike, and can be a sulfonamide-based compound such as acetazolamide,methazolamide, ethoxzolamide, clofenamide, dichlorphenamide,disuflamide, mefruside, chlorthalidone, quinethazone, furosemide,clopamide, tripamide, indapamide, clorexolone, metolazone, xipamide,bumetanide, piretanide, or X-54; a thiazide-based compound such ashydrochlorothiazide, methylclothiazide, benzylhydrochlorothiazide,trichloromethiazide, cyclopenthiazide, polythiazide, ethiazide,cyclothiazide, bendroflumethiazide, or hydroflumethiazide; aphenoxyacetic acid-based compound such as ethacrynic acid, tienilicacid, indacrinone, or quincarbate; triamterene; amiloride;spironolactone; potassium canrenoate; torasemide; MK-447; or traxanoxsodium, and is preferably a thiazide-based compound, and more preferablyhydrochlorothiazide.

The chemical name of hydrochlorothiazide is6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide, and hydrochlorothiazide as used herein encompasses apharmacologically acceptable salt thereof, and the salt can be, forexample, a hydrogen halide salt such as a hydrofluoride, ahydrochloride, a hydrobromide, or a hydroiodide; a nitrate; aperchlorate; a sulfate; a phosphate; a C1-C4 alkane sulfonate which maybe substituted with halogen such as a methanesulfonate, atrifluoromethanesulfonate, or an ethanesulfonate; a C6-C10 arylsulfonate which may be substituted with C1-C4 alkyl such as abenzenesulfonate or a p-toluenesulfonate; a C1-C6 fatty acid salt suchas acetate, malate, a fumarate, a succinate, a citrate, a tartrate, anoxalate, or a maleate; or an amino acid salt such as a glycine salt, alysine salt, an arginine salt, an ornithine salt, a glutamate, or anaspartate, and is preferably a hydrochloride, a nitrate, a sulfate, or aphosphate, and particularly preferably a hydrochloride.

Further, in the case where the above compounds have an asymmetriccarbon, the diuretic of the present invention also encompasses opticalisomers and mixtures of isomers thereof. Further, it also encompasseshydrates of the compounds.

In the invention, the phrase administered “simultaneously” is notparticularly limited as long as it is an administration form capable ofperforming administration at substantially the same time, however, it ispreferred to perform administration as a single composition.

In the invention, the phrase administered “separately at a timeinterval” is not particularly limited as long as it is an administrationform capable of performing administration separately at different times,however, for example, it refers to that first, an MR antagonist isadministered, and then, after a predetermined time, a calcium antagonistis administered, or first, a calcium antagonist or a diuretic isadministered, and then, after a predetermined time, an MR antagonist isadministered in the same manner as described above.

A pharmaceutical composition for administering simultaneously orseparately at a time interval the MR antagonist and the angiotensin IIreceptor antagonist, the calcium antagonist, or the diuretic of thepresent invention can further lower the blood pressure by allowing theMR antagonist and component (A), component (B), or component (C) to actas specifically described in the Examples of this description. Based onthe activity described above, the pharmaceutical of the presentinvention can be used for the prophylaxis or treatment (particularlytreatment) of hypertension, a heart disease [angina pectoris, myocardialinfarction, arrhythmia (including sudden death), heart failure, orcardiac hypertrophy], a kidney disease (diabetic nephropathy,glomerulonephritis, or nephrosclerosis), a cerebrovascular disease(cerebral infarction or intracerebral hemorrhage), or a vasculardisorder (arteriosclerosis, restenosis after PTCA, or peripheralcirculatory disturbance). Incidentally, by using the MR antagonist andthe angiotensin II receptor antagonist, the calcium antagonist, or thediuretic of the present invention in combination, a more excellenteffect is exhibited as compared with the case where each agent isadministered singly.

The MR antagonist and the angiotensin II receptor antagonist, thecalcium antagonist, or the diuretic serving as the active ingredients ofthe pharmaceutical composition of the present invention can be preparedin the form of separate unit dosage forms each containing a single agentalone, or can be prepared physically in the form of one unit dosage formby mixing these agents.

In the case where the pharmaceutical composition of the presentinvention is used as a prophylactic agent or a therapeutic agent for anyof the above-mentioned diseases, the MR antagonist and the angiotensinII receptor antagonist, the calcium antagonist, or the diuretic servingas the active ingredients of the pharmaceutical composition of thepresent invention can be administered orally in the form of a tablet, acapsule, a granule, a powder, a syrup, or the like, or parenterally inthe form of an injection, a suppository, or the like, which is producedaccording to a known method using the respective agents by themselves,or by using also a suitable pharmacologically acceptable additive suchas an excipient, a lubricant, a binder, a disintegrant, an emulsifier, astabilizer, a corrigent, or a diluent. Incidentally, the MR antagonist,and the components (A), (B), and (C) to be comprised in thepharmaceutical of the present invention are agents to be generallyadministered orally, and therefore, the pharmaceutical of the presentinvention is desirably administered orally.

Examples of the “excipient” to be used include organic excipientsincluding sugar derivatives such as lactose, white soft sugar, glucose,mannitol, and sorbitol; starch derivatives such as corn starch, potatostarch, pregelatinized starch, and dextrin; cellulose derivatives suchas crystalline cellulose; gum arabic; dextran; and pullulan; andinorganic excipients including silicate derivatives such as lightanhydrous silicic acid, synthetic aluminum silicate, calcium silicate,and magnesium metasilicate aluminate; phosphates such as calciumhydrogen phosphate; carbonates such as calcium carbonate; and sulfatessuch as calcium sulfate.

Examples of the “lubricant” to be used include stearic acid; stearicacid metal salts such as calcium stearate and magnesium stearate; talc;colloidal silica; waxes such as beeswax and spermaceti; boric acid;adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid;sodium stearyl fumarate; sodium benzoate; D,L-leucine; lauryl sulfatessuch as sodium lauryl sulfate and magnesium lauryl sulfate; silicatessuch as anhydrous silicic acid and silicate hydrate; and theabove-mentioned starch derivatives.

Examples of the “binder” to be used include hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, andcompounds similar to the above-mentioned excipients

Examples of the “disintegrant” to be used include cellulose derivativessuch as low-substituted hydroxypropyl cellulose, carboxymethylcellulose, calcium carboxymethyl cellulose, and internally crosslinkedsodium carboxymethyl cellulose; cross-linked polyvinylpyrrolidone; andchemically modified starches and celluloses such as carboxymethyl starchand sodium carboxymethyl starch.

Examples of the “emulsifier” to be used include colloidal clays such asbentonite and Veegum; metal hydroxides such as magnesium hydroxide andaluminum hydroxide; anionic surfactants such as sodium lauryl sulfateand calcium stearate; cationic surfactants such as benzalkoniumchloride; and nonionic surfactants such as polyoxyethylene alkyl ether,polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester.

Examples of the “stabilizer” to be used include p-hydroxybenzoate esterssuch as methyl paraben and propyl paraben; alcohols such aschlorobutanol, benzyl alcohol, and phenyl ethyl alcohol; benzalkoniumchloride; phenols such as phenol and cresol; thimerosal; dehydroaceticacid; and sorbic acid.

Examples of the “corrigent” to be used include sweeteners such as sodiumsaccharin and aspartame; acidulants such as citric acid, malic acid, andtartaric acid; and flavors such as menthol, lemon, and orange flavors.

Examples of the “diluent” to be used include materials generally used asa diluent such as lactose, mannitol, glucose, sucrose, calcium sulfate,calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose,water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, and mixturesthereof.

The doses of the mineralocorticoid receptor antagonist, the angiotensinII receptor antagonist, the calcium antagonist, and the diuretic servingas the active ingredients of the pharmaceutical composition of thepresent invention can vary depending on various conditions such as theactivities of the respective agents, and the symptoms, age, body weight,etc. of a patient. The doses vary depending on the symptoms, age, etc.,however, each agent can be administered at a dose of 0.1 mg (preferably0.5 mg) as a lower limit and 1000 mg (preferably 500 mg) as an upperlimit in the case of oral administration, and at a dose of 0.01 mg(preferably 0.05 mg) as a lower limit and 100 mg (preferably 50 mg) asan upper limit in the case of parenteral administration to a human adult1 to 6 times per day depending on the symptoms, and the agents can beadministered simultaneously or separately at a time interval.

Further, the ratio of the doses of the MR antagonist and the angiotensinII receptor antagonist, the calcium antagonist, or the diuretic servingas the active ingredients of the pharmaceutical composition of thepresent invention can also largely vary, but the weight ratio thereofcan be in the range of 1:1-10000 to 10000:1-10000, preferably in therange of 1:1-1000 to 1000:1-1000, more preferably in the range of1:1-100 to 100:1-100. Further, the doses in the case where themineralocorticoid receptor antagonist serving as the active ingredientof the pharmaceutical composition of the present invention is(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,the angiotensin II receptor antagonist is olmesartan medoxomil, thecalcium antagonist is amlodipine, and the diuretic ishydrochlorothiazide can vary depending on various conditions such as theactivities of the respective agents, and the symptoms, age, body weight,etc. of a patient, and therefore vary depending on the symptoms, age,etc., however, in the case of oral administration,(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamidecan be administered at a daily dose of 1.0 mg to 10 mg (preferably 2.5mg to 5 mg), olmesartan medoxomil can be administered at a daily dose of5 mg to 80 mg (preferably 10 mg to 40 mg), amlodipine can beadministered at a daily dose (on the free form basis) of 2.5 mg to 20 mg(preferably 5 mg to 10 mg), and hydrochlorothiazide can be administeredat a daily dose (on the free form basis) of 5 mg to 50 mg (preferably12.5 mg to 25 mg) to a human adult 1 to 6 times per day (preferably onceper day) depending on the symptoms.

Incidentally, in the case where the MR antagonist is used for theprophylaxis or treatment of hypertension in the present invention, thedose of the MR antagonist can be somewhat lower than in the case whereit is used as a pressure lowering agent which is its original usage, andthe dose thereof can be further decreased by the excellent effect ofcombined administration thereof with the angiotensin II receptorantagonist, the calcium antagonist, or the diuretic.

EXAMPLES

Hereinafter, the present invention will be described in further detailwith reference to Examples and the like, however, the scope of thepresent invention is not limited thereto.

Example 1 Test of Combined Administration of MR Antagonist andAngiotensin II Receptor Antagonist to Evaluate the Inhibitory Action onBlood Pressure Elevation

Male Dahl rats (DIS/Eis [Dahl-Iwai S], SPF grade, supplier: Japan SLC,Inc., salt-sensitive hypertensive rats) at 7 weeks of age were dividedinto groups (6 rats per group).

In a normal group and a control group, 0.5% methyl cellulose solutionwas orally administered for 6 weeks, and in the other groups, a testsubstance was orally administered for 6 weeks. The test substance wassuspended in 0.5% methyl cellulose solution and administered at a volumeof 2 mL/kg. Additionally, in the groups other than the normal group, an8% salt diet (FR-2 containing 8% NaCl, manufactured by Funabashi FarmCo., Ltd.) was given ad libitum from the start of administration of thetest substance. The composition of the groups and the administered testsubstances [in parentheses] are as follows.

Group 1: normal group

Group 2: control group

Group 3: compound (Ia) administration group [compound (Ia) (1.0 mg/kg)]

Group 4: olmesartan medoxomil administration group [olmesartan medoxomil(10 mg/kg)]

Group 5: combined administration group [compound (Ia) (1.0mg/kg)+olmesartan medoxomil (10 mg/kg)]

The results obtained by measuring systolic blood pressure using anoninvasive sphygmomanometer for rats and mice (BP-98A, Softron Co.,Ltd.) during the trough period at the 6th week of administration of thetest substance (on day 42 from the start of administration of the testsubstance) are shown in Table 1 (the values in the table represent mean±standard error).

TABLE 1 Systolic blood Administration group pressure (mmHg) Group 1:normal group 129 ± 5 Group 2: control group 219 ± 4 Group 3: compound(Ia) 170 ± 4 administration group Group 4: olmesartan medoxomil 202 ± 8administration group Group 5: combined administration 158 ± 3 group

With the combined administration of the MR antagonist and theangiotensin II receptor antagonist, an excellent pressure loweringaction (inhibition of blood pressure elevation) was confirmed.

Example 2 Test of Combined Administration of MR Antagonist and CalciumAntagonist to Evaluate the Inhibitory Action on Blood Pressure Elevation

Male Dahl rats (DIS/Eis [Dahl-Iwai S], SPF grade, supplier: Japan SLC,Inc., salt-sensitive hypertensive rats) at 7 weeks of age were dividedinto groups (6 or 9 rats per group).

In a normal group and a control group, 0.5% methyl cellulose solutionwas orally administered for 6 weeks, and in the other groups, a testsubstance was orally administered for 6 weeks. The test substance wassuspended in 0.5% methyl cellulose solution and administered at a volumeof 2 mL/kg. Additionally, in the groups other than the normal group, an8% salt diet (FR-2 containing 8% NaCl, manufactured by Funabashi FarmCo., Ltd.) was given ad libitum from the start of administration of thetest substance. The composition of the groups, the administered testsubstances [in parentheses], and the number of rats (n) per group are asfollows.

Group 1: normal group n=6

Group 2: control group n=9

Group 3: compound (Ia) administration group [compound (Ia) (0.1 mg/kg)]n=6

Group 4: amlodipine administration group [amlodipine (1 mg/kg)] n=6

Group 5: combined administration group [compound (Ia) (0.1mg/kg)+amlodipine (1 mg/kg)] n=6

The results obtained by measuring systolic blood pressure using anoninvasive sphygmomanometer for rats and mice (BP-98A, Softron Co.,Ltd.) during the trough period at the 6th week of administration of thetest substance (on day 41 from the start of administration of the testsubstance) are shown in Table 2 (the values in the table represent mean±standard error).

TABLE 2 Systolic blood Administration group pressure (mmHg) Group 1:normal group 138 ± 6 Group 2: control group 210 ± 2 Group 3: compound(Ia) 207 ± 7 administration group Group 4: amlodipine 207 ± 5administration group Group 5: combined administration 189 ± 9 group

With the combined administration of the MR antagonist and the calciumantagonist, an excellent pressure lowering action (inhibition of bloodpressure elevation) was confirmed.

Example 3 Test of Combined Administration of MR Antagonist and Diureticto Evaluate the Inhibitory Action on Blood Pressure Elevation andProteinuria

Male Dahl rats (DIS/Eis [Dahl-Iwai S], SPF grade, supplier: Japan SLC,Inc., salt-sensitive hypertensive rats) at 7 weeks of age were dividedinto groups (6 or 9 rats per group).

In a normal group and a control group, 0.5% methyl cellulose solutionwas orally administered for 6 weeks, and in the other groups, a testsubstance was orally administered for 6 weeks. The test substance wassuspended in 0.5% methyl cellulose solution and administered at a volumeof 2 mL/kg. Additionally, in the groups other than the normal group, an8% salt diet (FR-2 containing 8% NaCl, manufactured by Funabashi FarmCo., Ltd.) was given ad libitum from the start of administration of thetest substance. The composition of the groups, the administered testsubstances [in the parentheses], and the number of rats (n) per groupare as follows.

Group 1: normal group n=6

Group 2: control group n=9

Group 3: compound (Ia) administration group [compound (Ia) (0.3 mg/kg)]n=6

Group 4: hydrochlorothiazide administration group [hydrochlorothiazide(1 mg/kg)] n=6

Group 5: combined administration group [compound (Ia) (0.3mg/kg)+hydrochlorothiazide (1 mg/kg)] n=6

Systolic blood pressure was measured by using a noninvasivesphygmomanometer for rats and mice (BP-98A, Softron Co., Ltd.) duringthe trough period at the 6th week of administration of the testsubstance (on day 40 from the start of administration of the testsubstance). In addition, on day 41 from the start of administration ofthe test substance, urine collection for 24-hour was performed using ametabolic cage (2100-R, Watanabe Isolator Systems Co., Ltd.), and thedaily urinary protein excret ion per body weight was calculated.

The results are shown in Table 3 (the values in the table representmean±standard error).

TABLE 3 Daily urinary Systolic blood protein excretion Administrationgroup pressure (mmHg) (mg/kg/day) Group 1: normal group 150 ± 3 87 ± 5Group 2: control group 225 ± 6 447 ± 88 Group 3: compound (Ia) 196 ± 7190 ± 16 administration group Group 4: 212 ± 3 320 ± 65hydrochlorothiazide administration group Group 5: combined 189 ± 3 167 ±20 administration group

With the combined administration of the MR antagonist and the diuretic,an excellent pressure lowering action (inhibition of blood pressureelevation) and an excellent inhibitory action on proteinuria wereconfirmed.

Preparation Example 1

Tablet (fixed dosage) Compound (Ia)  5.00 mg Amlodipine besylate  13.89mg Pregelatinized starch 105.00 mg Crystalline cellulose 147.41 mgCarmellose sodium  15.00 mg Magnesium stearate  1.20 mg

A powder having the above formulation is mixed and tableted with atableting machine, thereby forming a tablet (300 mg/tablet). This tabletcan be sugar-coated as needed.

INDUSTRIAL APPLICABILITY

According to the present invention, a pharmaceutical for the prophylaxisor treatment of hypertension or a disease derived from hypertension isobtained. More specifically, a pharmaceutical for the prophylaxis and/ortreatment of hypertension, a heart disease [angina pectoris, myocardialinfarction, arrhythmia (including sudden death), heart failure, orcardiac hypertrophy], a kidney disease (diabetic nephropathy,glomerulonephritis, or nephrosclerosis), a cerebrovascular disease(cerebral infarction or intracerebral hemorrhage), or a vasculardisorder (arteriosclerosis, restenosis after PTCA, or peripheralcirculatory disturbance) is obtained.

1. A pharmaceutical for the prophylaxis or treatment of hypertension or a disease derived from hypertension, characterized by comprising (i) a mineralocorticoid receptor antagonist which comprises a substance selected from the group consisting of a compound represented by the following formula (I):

and an atropisomer thereof, and a pharmacologically acceptable salt thereof, and (ii) one or more components selected from the following components (A) to (C), for administration simultaneously or separately at a time interval: (A) one or more angiotensin II receptor antagonists; (B) one or more calcium antagonists comprising a substance selected from the group consisting of a 1,4-dihydropyridine-based compound and a pharmacologically acceptable salt thereof; and (C) one or more diuretics.
 2. A pharmaceutical for the prophylaxis or treatment of a disease selected from the group consisting of hypertension, a heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, a kidney disease, diabetic nephropathy, glomerulonephritis, nephrosclerosis, a cerebrovascular disease, cerebral infarction, intracerebral hemorrhage, and a vascular disorder (arteriosclerosis, restenosis after PTCA, or peripheral circulatory disturbance), comprising one or more components selected from component (A), component (B), and component (C), and the mineralocorticoid receptor antagonist according to claim 1 as active ingredients.
 3. The pharmaceutical according to claim 1, wherein the pharmaceutical is in the form of a pharmaceutical composition.
 4. The pharmaceutical according to claim 1, wherein the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate.
 5. The pharmaceutical according to claim 1, wherein the calcium antagonist is a calcium antagonist selected from the group consisting of azelnidipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine, clevidipine, lacidipine, and nilvadipine.
 6. The pharmaceutical according to claim 1, wherein the calcium antagonist is amlodipine.
 7. The pharmaceutical according to claim 1, wherein the diuretic is a diuretic selected from the group consisting of hydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide, trichloromethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide, and hydroflumethiazide.
 8. The pharmaceutical according to claim 1, wherein the diuretic is hydrochlorothiazide.
 9. The pharmaceutical according to claim 1, wherein the mineralocorticoid receptor antagonist is (S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide represented by the following formula (Ia):

and the calcium antagonist is amlodipine.
 10. The pharmaceutical according to claim 1, wherein the pharmaceutical is formulated as a single preparation. 